Submissions for variant NM_000057.4(BLM):c.4077-10C>T

gnomAD frequency: 0.00233  dbSNP: rs145310008

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000123854	SCV000167197	benign	not specified	2014-02-26	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227864	SCV000283147	benign	Bloom syndrome	2025-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000227864	SCV000394434	likely benign	Bloom syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Eurofins Ntd Llc (ga)	RCV000123854	SCV000855793	likely benign	not specified	2017-08-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000123854	SCV000918646	benign	not specified	2019-12-23	criteria provided, single submitter	clinical testing	Variant summary: BLM c.4077-10C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00057 in 250972 control chromosomes, predominantly at a frequency of 0.0079 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BLM causing Bloom Syndrome phenotype (0.0035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.4077-10C>T in individuals affected with Bloom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=1; likely benign, n=1, VUS, n=1). Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000227864	SCV001139717	likely benign	Bloom syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000123854	SCV002046909	benign	not specified	2021-04-29	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000123854	SCV002071186	likely benign	not specified	2020-10-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257453	SCV002533040	likely benign	Hereditary cancer-predisposing syndrome	2021-03-14	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000227864	SCV005879194	likely benign	Bloom syndrome	2024-05-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000227864	SCV002090649	likely benign	Bloom syndrome	2017-08-09	no assertion criteria provided	clinical testing